Indirect evidence suggests that brain serotonin (5-HT) alterations occur in women with anorexia nervosa (AN) when they are underweight and after recovery. This competitive renewal will use new technologies that offer the potential of direct characterization of dynamic relationships between 5-HT receptor function and human behavior. We will assess 5-HT1A and 5-HT2A receptors. A defect in either may contribute to trait-related increased 5-HT neurotransmission associated with core AN symptoms, such as restricted feeding, obsessions with order and perfectionism, harm avoidance and negative affect. Our last funding period supports the possibility that starvation-induced changes may reduce 5-HT neuronal activity, which in turn reduces dysphoric affective states. Such receptor changes may also shed light on failure to respond to SSRIs. Over 4 years 3 groups of women (18 to 45 years old) will be studied: 1) 30 AN women who are underweight; 2) 30 women who are recovered (greater than 1 year normal menses, no bingeing and purging, and healthy and stable weight) from AN; 3) 30 healthy control women (CW). Each AN cohort will consist of 15 restricting-subtypes and 15 binge- eating/purging subtypes. In Aim 1 Positron Emission Tomography (PET) imaging and [18F]altanserin will assess 5-HT2A postreceptor binding. Preliminary data support the possibility that recovered AN women will have a reduction of orbitofrontal 5-HT2A receptor binding associated with evidence of increased extracellular 5-HT. In comparison, underweight AN should have opposite findings. In Aim 2 PET imaging and [11C]WAY100635 will assess 5-HT1A receptor binding. Knockout gene studies in mice support the hypothesis that a malfunction of pre-synaptic raphe autoreceptors could contribute to increased 5-HT activity and behavioral symptoms in AN. Thus 1A binding may not change with state of the illness. Our last funding period found that a polymorphism (-1438G/A) in the promoter region of the 5-HT2A receptor gene was associated with AN. Aim 3 is a pilot study that will explore whether this or other 5-HT related polymorphisms, are associated with altered binding on PET or with behavioral symptoms. Aim 4 will test whether core AN symptoms or impulse control are related to 5-HT neuronal activity. The understanding of whether a biologic vulnerability, such as a 5-HT disturbance, occurs in AN may contribute to developing new treatment interventions for this often chronic and deadly disorder.